This invention relates to locally administrable, biodegradable and sustained-release pharmaceutical compositions for periodontitis, and its process for preparation thereof, which can show continuous drug effect for a long time by controlling the release time and by making the drug remain in the periodontal pocket for a prolonged time wherein they are prepared by i) making a microsphere containing the physiologically active substance, ii) making a mixture of the microspheres and water-soluble polymer such as polysaccharides iii) making the mixture into the form of film or strip or/and iv) coating the film or strip with aqueous solution of cation such as calcium and barium chlorides.
Periodontitis is an inflammation of the teeth supporting tissue caused by bacterial toxin, which is a metabolizing product of oral bacteria. If periodontitis in the initial stage that is gingivitis is not treated properly, it will develop into severe periodontitis with swelling gingiva, bleeding and bad breath. If periodontitis goes on, the collagen supporting the periodontal membrane is destroyed, and alveolar bone under the teeth is resolved. As a result, periodontal ligament is separated, and a periodontal pocket is formed, and in severe cases, it will develop into advanced periodontal disease which can lead to loss of teeth. Most of the germs causing periodontitis are anaerobic gram-negative bacteria, and they secrete collagenase ,which destroy ligament that is connective tissue of the periodontal membrane, and metabolite from above reaction cause periodontitis.
For prevention and treatment of the advanced periodontal disease, removal of the plaque in the periodontal pocket is essential. The methods for removal of the-bacterial plaque can be divided into apparatotherapy and chemotherapy. Apparatotherapies include scaling and root planing, and require the patient's ability to control plaque continuously, but have the disadvantage that apparatotherapies have a limited effect on the part at which it is difficult to brush teeth due to anatomical reason. For supplement of the above disadvantage of apparatotherapies, the plaque control using chemotherapies has been studied and it is reported that chemotherapies are very effective on the removal of bacteria which live in the deep part where instruments are difficult to reach.
The most important thing in the clinical use is to retain the effective concentration of the active substance which control plaque in the bacterial invasion site for a long time without side-effect. The examples of chemical method include irrigating the invaded region with an antibiotic solution, and administering antibiotics systemically. It is known that local administration of antibiotics has a limited effect on the removal of the bacteria causing periodontal disease because antibiotics cannot reach the deep part of the subgingival area or cannot last for enough time. It is reported that the systemic administration is effective on the treatment for the periodontal disease, but in the case of the systemic administration in order to maintain the effective concentration at the infected region it is required that a large dosage of medicine is administered and subsequently side effects result, for example, the appearance of resistant bacteria and undesired action to intestinal bacteria. Therefore, to overcome this defect, the research for the direct administration into the periodontal pocket has been conducted, and it is reported that if tetracycline is administrated locally, only 1/1000 dosage of the systemic administration can bring the same effect (Goodson, J. M. et al., J. Periodontol, 56 265-272, 1985).
In order to bring the maximum effect and minimum side-effect, it has been attempted to develop the local drug delivery system using the controlled release system of physiologically active substances such as antibiotics.
There are a few problems that must be solved to treat the periodontitis by a local drug delivery system.
First, a carrier is necessary to transport a physiologically active substance such as antibiotics to the periodontal pocket. A large number of carriers developed so far are substances not absorbed biologically, which must be removed after the drug is released completely and if not, they irritate the periodontal tissue and inhibit the regeneration of the periodontal tissue.
According to U.S. Pat. No. 5,599,553, it is reported that a pharmaceutical preparation composed of minocycline HCl and polycaprolactone in the form of strip can release the active substance for 7 days in the periodontal pocket. In this case polycaprolactone must be removed after the drug is released completely because it takes too long a time to be decomposed in the body.
Second, to treat the periodontitis, effective concentration of the active substance in the periodontal pocket must be maintained for a long time. It is reported that to treat the periodontitis the effective concentration of antibiotics such as monocycline HCl must be maintained for at least 7 to 10 days (Lawter J. R. et al., Int. sym. cont. Rel, Bioact. Mater., 230-31, 1990). It is reported that the therapeutic agent should be retained as long as possible because dental disease is generally chronic (Friedman M. et al., Pharmaceutical Research, Vol. 7, No. 4, 313-317, 1990). In addition, it is known that, if administered orally, administration for more than two weeks is effective for the treatment for periodontitis (Lilijenberg B et al., J. Clin. periodontol., 7, 48-61, 1980).
According to U.S. Pat. No. 4,933,182, a pharmaceutical preparation wherein polymeric microparticles containing one or more substances is dispersed into the continuous phase of water soluble polymer. This has an advantage that it can release substance in an independent pattern and it does not give an unpleasant feeling to the patients, but it has disadvantage that administration should be made often because the release of substance is completed in about 6 hours.
Third, it is needed that the process of administration is convenient and quantitative on the basis of the amount of active substance.
According to U.S. Pat. No. 4,175,326, a pharmaceutical preparation containing the active substance in a hollow fiber device made up of cellulose acetate is reported. In order to administer this preparation into the periodontal pocket, fiber should be cut into the length for the dosage, and then the cut fiber must be coiled around the teeth, and then it must be administered in the way of pushing it into the periodontal pocket. This method has disadvantage that it is inconvenient to administer drug into the periodontal pocket quantitatively.
According to WO A1 92/07555 and U.S. Pat. No. 5,324,520, an in situ gel has been reported which is in a liquid state before administration and becomes a little hardened state after administration. Because the formulations are in a liquid state before administration, a special administering tool is needed in the form of a syringe and these formulations also have disadvantage that it is inconvenient to administer quantitatively.
In order to satisfy the most important things for treating the periodontitis, that is to say, biodegradation and continuous drug release, microspheres made up of biodegradable polymer has been provided which is dissolved when it is administered into the periodontal pocket and releases drug continuously. For example, it is reported that they suspensed PLGA microspheres including tetracycline in Pluronic F 127 gel and then inserted the prepared formulation in the peridontal pocket (EP A1 244118). In addition, it is reported that they can maintain the effective concentration in the periodontal pocket for 14 days by inserting microsphere containing minocycline and PLGA (Lawter J. R. et al., Int. Symp. Cont. Rel. Bioact. Mater., 230-231, 1990), and filed a patent application therefor. The formulation for treating periodontitis using such biodegradable microspheres can retain the effective drug concentration in the periodontal pocket for a long time by single dose, and the feeling of foreign substance does not exist because the formulation was prepared by microparticle, and there is no need to remove after treatment because the formulation is biodegradable. However, since microspheres prepared in the form of gel can not last for a long time due to its hydrolytic property, there is inconvenience that it should be prepared just before use, and that a special administering tool is needed in order to insert gel into the periodontal pocket. And it is difficult to administer quantitatively and accurately when we insert the microspheres directly into the periodontal pocket.
Therefore, in order to develop ideal formulations for periodontitis, it is desirable that a biodegradable substance is used to control drug release, the effective drug concentration is maintained continuously and the administration is convenient for patients.
The present inventors have been conducted the continuous study for the ideal formulation for periodontitis, and we found that if the biodegradable microspheres containing physiologically active substance for periodontitis is mixed with the hydrogel of water soluble polymer and then the mixture is made into the form of thin film or strip, and this film or strip is inserted into the periodontal pocket, it will show the continuous effect for a long time, since water soluble polymer is decomposed slowly, on contacting saliva and the gingival crevice fluid, and subsequently only the microspheres became left alone in the periodontal pocket and these microspheres release the active substance continuously. In addition, the inventors discovered that when the film or strip is spray-coated with aqueous solution of cation salt such as Ca.sup.2+ or Ba.sup.2+, disintegration time can be controlled effectively.